Mitogen-activated protein kinase (MAPK) is relevant to many cancers. MAPKs specifically phosphorylate serine/threonine residues of proteins, that are activated by a variety of external stimuli (for example, mitogens and growth factors) to manifest its actions inside the cell. The activation of MAPKs regulates many functions of the cells with physiological implications such as cell growth, survival, apoptosis, differentiation, proliferation and gene expression. (1)
MEK 1 and 2 are two human kinases in the middle of the classical MAPK-cascade involving upstream RAS-RAF and downstream ERKs. This signal transduction cascade resulting in phosphorylation of ERKs is extensively studied in cancer pathology. The phosphorylated-ERK upon its translocation to nucleus activates several transcription factors to induce the expression of many genes required for cell survival and proliferation. (2) Because of the very high selectivity conferred on MEKs to phosphorylate only ERK1 and ERK2, targeting its inhibition offers an attractive strategy for anti-cancer drug discovery. (3)
In addition, the mechanism of action of the known MEK inhibitors such as PD98059 and U0126 is non ATP-competitive (binding to allosteric site) and thus may have least side effects in clinics. Few of the MEK inhibitors currently undergoing clinical studies, (4,5). include AZD-6244, (Array Biopharma, Astra Zeneca), RDEA-119 (Ardea Biosciences, Bayer, see A. Maderna et al, U.S. Pat. No. 7,759,518), in combination with sorafenib, displaying a significant response in sorafenib resistant hepatoma cells, and XL-518 (Exelixis) for solid tumors.
Identification of inhibitors of mitogen-activated protein (MAP) protein kinases, especially MEK1 and/or MEK2 inhibitors, is a widely active area in pharmaceutical research because of the potential use of such inhibitors as drugs to treat a variety of disease states affected by such inhibition. Comprehensive reviews of the state of the art in this field is found in S. Price, Expert Opin. Ther. Patents (2008) 18 (6), 603-627 and C. Fremin, S. Meloche, Journal of Hematology and Oncology 2010, 3:8.
Despite current progress in MEK inhibitor research, it would nevertheless be highly beneficial to discover additional MEK inhibitors with improved pharmacological properties such as potency, oral bioavailability, half-life, and low CNS penetration for the treatment of various types of cancer. Compounds with such properties lead to more efficacious treatments of cancers, while minimizing undesirable side effects.
Furthermore, in additional to their potential as anti-tumor agents, MEK inhibitors are described in the art as having potential use for the treatment of anti-inflammatory diseases, chronic obstructive pulmonary disease, cardio-facio-cutaneous syndrome, and influenza. Well over 50 patent families exist which describe various compounds purported to have MEK activity.